Worried about waiting to have children?

Edit: It’s been pointed out that my post is largely from the perspective of the father/child. Some relevant reading for mothers weighing this question includes decreasing chances of becoming pregnant as you age (http://pensees.pascallisch.net/?p=1010) and increasing chances of fetal loss as mothers age (http://www.bmj.com/content/320/7251/1708 …I’ve attached the relevant (rather dismaying) graph at the bottom of this post). For the sake of your kid’s mental health, however, read on…

Edit 2: A reader pointed out that mental retardation, which I didn’t touch on, HAS been linked with maternal age (even though schizophrenia/autism have not). I added another relevant graph at the end of this post. Recurring theme: risks increase for mothers older than 35.

I’m a big fan of science that has an effect on our everyday lives. Of course, I’m a big fan of science in general, but in this case what I’m specifically referring to are studies I can tell friends (or enemies) about and change their lives for the better (or worse). This is largely why I personally decided to switch fields from molecular biophysics to cognitive neuroscience—I wanted to study things with more every day, macroscopic applicability.

I came across this short paper on twitter and think it has some implications that will be interesting to pretty much anyone. More so, I hope it alleviates some worry for my NYC/city-living/northern brethren out there, who tend to skew older in their decision of when to have children. It’s called “The importance of father’s age to schizophrenia risk” and was published last May in Molecular Psychiatry. It analyzes a dataset I had not heard of before—even though it appears to be a big deal in genetics research—called the Danish nationwide registers. This database of all Danish people born from 1955-1996, which is apparently linked to their medical information, provides an incredible sample size to look at diseases across populations.

Before I get into the details of what this study shows, a little background on what we know about older parents. I get the impression the status quo is that having children as an older mom is risky for chances of cognitive disease in the progeny (whether it be schizophrenia, autism, ADHD, etc.—such higher-level cognitive diseases are not easy to define and MANY seem to be related). However, this never made much sense, since these kinds of diseases are thought to come from genetic mutations, and females are born with their lifetime supply of eggs so there’s no reason to think that the female germ line will be degraded as the mother ages. Therefore blame has come to rest on the (older) fathers, who produce new sperm every 15-16 days (I’ve read these numbers in at least 3 places although can’t find the original source. For argument’s sake we can at least assume men regenerate their sperm throughout life). This results in about two point mutations per year in the germline of men. And since there’s strong correlative evidence in older fathers having a greater chance of schizophrenic or autistic children, it seems like a reasonable conclusion that these mutations accumulated throughout a dad’s life progressively make his odds worse for having a normal-functioning child the older he gets.

Wait wait don’t tab over to match.com and settle just yet!! We still have the results of this aforementioned Danish study. They took all second or later born children from the 40 year period I mentioned and determined if they developed schizophrenia from 1970-2001 (at least 15 years after birth). 8,865/1,334,883 (0.66%) of this group were diagnosed as such. Fortunately there’s only one figure in this paper, so I’ll just go ahead and show it. First, as shown in blue in Figure a below, even taking only these second or later born children, they reproduce the previously found association between schizophrenia and increasing paternal age at the birth of this child (proband means the child with schizophrenia, in this case). Older father==higher incidence of schizophrenia==confirmed.

schizo

(from Molecular Psychiatry)

Now, you’ll notice in green they also graphed the father’s age when he had his first child. This is a little confusing, so I’ll try to spell it out (in the present tense, so it sounds FRESH). Take the 8,865 schizophrenic children born second or later. Now, look at the age of their dad when the firstborn came from these same parents. What the authors find is that there’s a greater incidence of schizophrenia (in later children) when dads had their first child at an older age.

The second graph (Figure b) makes this clearer. Again, this is a graph showing the incidence of schizophrenia in future kids, but this time shows the age of the dad when he had his firstborn kid (different colors) and the age when he had his future kid that has schizophrenia (Paternal age on the bottom axis). To explain this intuitively, let’s focus on the blue line. If a dad has his first child <24 years old, no matter what children he has in the future there is no indication of increased schizophrenia risk (the line stays near the population average value of 1). Now, the black line: if a dad has his first child after 50 years old, the chances of his later children having schizophrenia is 2.5x more likely. For the orange line, having a first child after 40 made the chance of a later child having schizophrenia enhanced by ~1.5x (note: it’s likely there was an enhancement of firstborn children with schizophrenia in these older dads too, but this has already been shown and is not what they’re interested in proving).

You probably understand the data by now, but what does this mean? As explained above, if dads were having schizophrenic children because they were gaining mutations over time, you’d expect someone that had multiple kids to have each successive kid increase in the chance of schizophrenia. The blue line in Figure b disputes this. Instead, when a dad doesn’t have any children until he is quite old, the chances of schizophrenia increase. This implies that there’s something inherently wrong with fathers who are unable to have children until later in life. This could be for a lot of reasons, but I’m willing to guess this doesn’t have to do with successful, career-driven people making conscious decisions not to start a family. What seems more plausible is that these older fathers are people with a harder time fitting in socially and finding a partner willing to have their child (or maybe it’s just that someone that suddenly decides to have his first child at 50 has a few screws loose). While I’m out on this interpretation limb, the factors making it difficult for such people to find a mate might well be a mild or precursor form of a cognitive disease like schizophrenia, the genetics of which would lead to a better chance than average of more obvious, full-blown symptoms expressing themselves in progeny. For me this fits into the theoretical framework of the genetics of emergent phenotypes, wherein multiple assaults on the genetic system can lead to following worse and worse pathways that results in cognitive disorder (here’s a great read for an explanation of the genetics of emergent phenotypes).

These results are great for us never-want-to-settle-down types, right? I’d like to think I choose not to settle down as I build my career, and as I delay potential progeny, my normative fecundity abilities aren’t dwindling away. I mean two random mutations a year can’t be that bad, right? It also means I don’t have to worry about freezing my sperm, as was suggested in Nature. Although not being able to beat my child in basketball when he’s 10 (and I’m 60) would hit me hard for more egotistical reasons, so I’m not exactly suggesting to wait too long.

For those not yet satisfied, a few more thoughts:

If you’re the questioning sort like me you might be wondering if there could be another biological force at play influencing these results. I agree that ‘age of father when he has his first kid’ isn’t the most satisfying, quantitative result. This study did account for the following factors though: “Incidence rate ratios were adjusted for age, sex, calendar time, birth year, maternal age, maternal age at her first child’s birth, degree of urbanization at the place of birth and history of mental illness in a parent or sibling.” Further, a very recent study (2014) out of Johns Hopkins I just came across while researching this topic came to a similar conclusion: that de novo mutations from the father are likely not the cause of increased schizophrenia risk in older fathers. Further confirmation that waiting to have kids doesn’t look like such a bad idea.

These controlled conditions aside, I came up with one alternate biological theory that I (just now after writing all of this) realized is actually supported by this 2014 study. One of the pillars of the genetic basis for homosexuality is the “birth order effect,” wherein each additional male child from one mother is 33% more likely to be gay. The hypothesis for this effect is called the “maternal immunization hypothesis.” In short, the mother is thought to respond to hormones from the in utero male child, which are novel to her as they’re from the male chromosome, and her body begins an immune response by forming antibodies to fight these invaders. Theoretically such antibodies could make it back into the developing male brain and alter the chemistry of maleness in the developing fetus.

Now you can imagine a similar process happening for any child in the womb. No matter what, when there are foreign genes present (in fact the placenta—which fights with the mother’s body for resources—actually comes from the father’s genes), the mother’s body could mount some kind of immune response. And with each successive child, the response could become stronger in the mother and affect the developing brain of her later-born children. And indeed, this 2014 study finds that birth order is more important for the mom than the dad (which makes some sense since the sperm don’t know about birth order, but the mother’s body could certainly be keeping track). To quote the paper: “The strong maternal age association might suggest that parity [birth order] adversely influences intrauterine development, and obstetrical complications (OCs) are also a risk factor for schizophrenia.” I left that last part in there to mention one more thing found to be associated with schizophrenia: problems in the physical birth of the child. In this case schizophrenic children are more likely when they are firstborns, although this is probably not saying very much since anyone with such complications is less likely to have more children (which would have theoretically been at a higher risk for birth complications and therefore schizophrenia as well).

The fact is: assaults on the brain at any point in development could lead it down the wrong path and support the emergence of cognitive disorders I mentioned earlier. The 2014 paper even points out that schizophrenia could be fostered by bad parenting after birth (again by older parents still—those effects are real), truly broadening the scope of the developmental window for diseases like schizophrenia. So, as it is with most things as complicated as cognitive disorders, there probably isn’t one cause and there are probably a lot of ways to get there. Hopefully new science will narrow our knowledge of these paths so we can make more informed decisions on how to live our lives and raise our families. I, for one, after reading this work, am not so concerned about popping out children any time soon…which is also probably not the right way to put it since I’m a guy.

Edit 1:

2014-03-10 13_27_09-Maternal age and fetal loss_ population based register linkage study _ BMJ(from BMJ)

Again from the Danish registry data with 634,272 women and 1,221,546 pregnancy outcomes. The wintergreen line indicates mothers are not at much increased risk until 35. I’m dismayed by the amount of fetal loss in general! The authors point out that there might be a greater chance of older mothers being admitted to the hospital, so hopefully these numbers are skewed a little high. It’s also pointed out in the comments that many Danish women smoke and I don’t think they correct for that. More recent numbers of fetal loss in America don’t look nearly this bad: http://www.cdc.gov/nchs/data/databriefs/db169.htm  

Edit 2:

2014-03-10 19_28_37-Maternal_age-specific_live_birth_prevalence_of_Down's_syndrome_in_the_United_Sta

(from Wikipedia)

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